Steroespecific preparation of chiral 1-aryl- and 1-heteroaryl-2-substituted ethyl-2-amines

ABSTRACT

This invention is directed to methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2-position, and to intermediates to the substituted ethyl-2-amines.

This application is a divisional application of U.S. patent applicationSer. No. 09/266,641, filed Mar. 11, 1999, U.S. Pat. No. 6,127,550 whichapplication is a continuation application of International PatentApplication No. PCT/US97/15729, filed Sep. 10, 1997, which, in turn,claims priority of U.S. Provisional Application No. 60/026,005, filedSep. 12, 1996, now abandoned.

FIELD OF THE INVENTION

This invention is directed to new methods for stereospecificallypreparing [(1-optionally substituted aryl)- or (1-optionally substitutedheteroaryl)]-2-substituted ethyl-2-amines, having chirality at the2-position.

The invention is directed also to new intermediates that are useful forpreparing substituted ethyl-2-amines.

The substituted ethyl-2-amines, and intermediate compounds therefor, areuseful as intermediates in the synthesis of cardiovascular agents,including antihypertensive agents, anti-ischemic agents,cardioprotective agents which ameliorate ischemic injury or myocardialinfarct size consequent to myocardial ischemia, and antilipolytic agentswhich reduce plasma lipid levels, serum triglyceride levels, and plasmacholesterol levels.

For example, the substituted ethyl-2-amines are useful as intermediatesin the preparation of antihypertensive and anti-ischemic heterocyclyladenosine derivatives and analogues as disclosed in U.S. Pat. No.5,364,862. They are useful also in the preparation ofN₉-cyclopentyl-substituted adenine derivatives reported to be adenosinereceptor ligands, and to be useful in treating cardiovascular conditionssuch as hypertension, thrombosis and atherosclerosis, and also intreating central nervous system conditions comprising psychoticconditions such as schizophrenia, and convulsive disorders such asepilepsy, as disclosed in U.S. Pat. No. 4,954,504. They are useful alsoin the preparation of N-6 and 5′-N substituted carboxamidoadenosinederivatives which have beneficial cardiovascular and antihypertensiveactivity as reported in U.S. Pat. No. 5,310,731.

REPORTED DEVELOPMENTS

Stereospecific preparation of chiral optionally substitutedheteroaryl-2-substituted ethyl 2-amines by reaction of heteroaryl anionswith 2-substituted ethylene oxides, and subsequent stereospecificconversion of the resulting chiral ethyl alcohol to the amine has beenreported by Spada et al., in U.S. Pat. No. 5,364,862.

Facilitation of acidolytic cleavage reactions, for example the removalof various protecting groups, in the presence of electrophilicscavengers has been reported. Deprotection ofN^(G)-mesitylene-2-sulfonylarginine is reported by Yajima et al., Chem.Pharm. Bull. 26 (12) 3752-3757 (1978). Removal of the protecting groupof O-benzyl serine, threonine, and tyrosine, and deprotection ofN^(e)-benzyloxycarbonyllysine is reported by Kiso et al., Chem. Pharm.Bull. 28 (2) 673-676 (1980). Deprotection procedures for thep-toluenesulfonyl and p-methoxybenzenesulfonyl groups from the N^(im)function of histidine is reported by Kitagawa et al., Chem. Pharm. Bull.28 (3) 926-931 (1980).

SUMMARY OF THE INVENTION

The present invention is directed to methods for stereospecificallypreparing [(1-optionally substituted aryl)- or (1-optionally substitutedheteroaryl)]-2-substituted ethyl-2-amines, having chirality at the2-position, comprising reacting a 2-amino-2-substituted ethyl alcohol,having chirality at the 2-position, with an [(optionally substitutedaryl)- or (trihalomethyl) sulfonyl]-halide or anhydride in the presenceof a base to form an [(N-arylsulfonyl)- or(N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality atthe 2-position.

DETAILED DESCRIPTION

As used above, and throughout the description of this invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

“Aryl” means phenyl or naphthyl.

“Optionally substituted aryl” means an aryl group which may besubstituted with one or more aryl group substituents. Examples of arylgroup substituents include alkyl, alkoxy, amino, aryl, heteroaryl,trihalomethyl, nitro, carboxy, carboalkoxy, carboxyalkyl, cyano,alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, andcarbamoyl. Preferred aryl group substituents include halo, hydroxy,alkyl, aryl, alkoxy, trihalomethyl, cyano, nitro, and alkylmercaptyl.

“Heteroaryl” means about a 4 to about a 10 membered aromatic ringstructure in which one or more of the atoms in the ring is an elementother than carbon, e.g., N, O or S. Examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinolinyl,quinazolinyl, imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, andbenzothiazolyl. A preferred heteroaryl group is thienyl.

“Optionally substituted heteroaryl” means that the heteroaryl group maybe substituted by one or more heteroaryl group substituents. Examples ofheteroaryl group substituents include alkyl alkoxy, alkylamino, aryl,carbalkoxy, carbamoyl, cyano, halo, heteroaryl, trihalomethyl, hydroxy,mercaptyl, alkylmercaptyl and nitro. Preferred heteroaryl groupsubstituents include halo, hydroxy, alkyl, aryl, alkoxy, trihalomethyl,cyano, nitro, and alkylmercaptyl.

“Halogen” (“halo”, “halide”) means chlorine (chloro, chloride), fluorine(fluoro, fluoride), bromine (bromo, bromide) or iodine (iodo, iodide).“Alkyl” means a saturated aliphatic hydrocarbon group which may bestraight or branched and have about 1 to about 20 carbon atoms in thechain. Preferred alkyl groups may be straight or branched and have about1 to about 10 carbon atoms in the chain. Lower alkyl means an alkylgroup which may be straight or branched having about 1 to about 6 carbonatoms, such as methyl, ethyl, propyl or tert-butyl. Branched means thata lower alkyl group is attached to a linear alkyl chain.

“Aralkyl” means an alkyl group substituted by an aryl group. “Optionallysubstituted aralkyl” means that the aryl group of the aralkyl group maybe substituted with one or more aryl group substituents.

“Heteroaralkyl” means an alkyl group substituted by a heteroaryl group.“Optionally substituted heteroaralkyl” means that the heteroaryl groupor the heteroaralkyl group may be substituted with one or more arylgroup substituents.

“Electrophilic scavenger” means an agent that can have a promotingeffect on acidolytic cleavage reactions, for example, as described byYajima et al., Chem. Pharm. Bull. 26 (12) 3752-3757 (1978), Kiso et al.,Chem. Pharm. Bull. 28 (2) 673-676 (1980), and Kitagawa et al., Chem.Pharm. Bull. 28(3)926-931 (1980).

An embodiment according to the invention is directed to the reaction ofa 2-amino-2-substituted ethyl alcohol with a sulfonyl halide oranhydride, preferably in the presence of an aprotic organic solvent.Aprotic organic solvents which are suitable for the reaction includeaprotic organic ethers, aromatic hydrocarbons, heteroaromatichydrocarbons, aliphatic hydrocarbons, and aprotic organic amides. Moreparticularly, examples of suitable aprotic organic solvents includediethyl ether, tert-butyl methyl ether, isopropyl methyl ether,diisopropyl ether, tetrahydrofuran, tetrahydropyran, and dioxan. In aspecial embodiment of methods according to the invention, the preferredaprotic organic solvent is tert-butyl methyl ether.

The reaction with the sulfonyl halide or anhydride takes placepreferably at a temperature in the range of from about 25° C. to about90° C.; more preferably from about 25° C. to about 40° C.

Suitable sulfonyl halides and anhydrides include phenyl-, tol-4-yl-,2,4,6-trimethylphenyl-, 2,4-dimethylphenyl-, 4-methoxyphenyl-,4-nitrophenyl-, 4-bromophenyl-, naphth-1-yl-, naphth-2-yl-, andtrifluoromethyl-sulfonyl chloride and anhydride. In a special embodimentof methods according to the invention, a preferred sulfonyl chloride isp-toluenesulfonyl chloride (i.e., tol-4-yl sulfonyl chloride).

According to the invention, the reaction of the 2-amino-2-substitutedethyl alcohol with the sulfonyl halide or anhydride takes place in thepresence of a base. Bases which are suitable for the reaction includeaqueous alkali metal hydroxides, aqueous alkali metal carbonates, andaprotic organic amines. More particularly, examples of suitable alkalimetal hydroxides include sodium hydroxide, potassium hydroxide, andlithium hydroxide; examples of suitable alkali metal carbonates includepotassium carbonate, sodium carbonate, and cesium carbonate; andexamples of suitable aprotic organic amines include triethylamine,diisopropyl ethyl amine, N-methylmorpholine, and pyridine. In a specialembodiment of methods according to the invention, a preferred base isaqueous sodium hydroxide.

Another embodiment according to the invention is directed to thereaction of the [(N-arylsulfonyl)- or(N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality atthe 2-position, which is formed from the reaction of the2-amino-2-substituted ethyl alcohol with the sulfonyl halide oranhydride, with an [(optionally substituted aryl)- or (optionallysubstituted heteroaryl)] lithium compound to form the lithium salt of an[(N-optionally substituted aryl)- or(N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or(optionally substituted heteroaryl)]-2-substituted alkyl-2-amine havingchirality at the 2-position. In a special embodiment of the invention,the lithium salt formed in the reaction is isolated as a solid.

Organolithium compounds may exist as tetramers, hexamers, and higheraggregates in hydrocarbon and ether solvents, as described, for example,by Carey, F. A., and Sundberg, Richard J., Advanced Organic Chemistry,Plenum Press, New York (2d ed. 1984), and Fraenkel et al., J Am. Chem.Soc. 102, 3345 (1980). Formation by methods according to the inventionof such aggregates of the lithium salts, and the aggregates so-formedare contemplated by and included in the invention.

The reaction to form lithium salt takes place preferably in an aproticorganic solvent. Aprotic organic solvents which are suitable for thereaction include aprotic organic ethers, aliphatic hydrocarbons, andaromatic hydrocarbons. In a special embodiment of methods according tothe invention, a preferred aprotic organic solvent is an aprotic organicether and, more particularly, tert-butyl methyl ether.

The formation of the lithium salt takes place preferably at about −80°C. to about 50° C.; more preferably at about −40° C. to about 50° C.

Yet another embodiment according to the invention is directed to thetreatment of the lithium salt of an [(N-optionally substituted aryl)- or(N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or(optionally substituted heteroaryl)]-2-substituted alkyl-2-amine havingchirality at the 2-position with one or more strong acids in thepresence of an electrophilic scavenger. This treatment takes placepreferably at a temperature range of about 45° C. to about reflux.

Strong acids which are suitable for the treatment includemethanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonicacid, trichloromethane sulfonic acid, trichloroacetic acid, sulfuricacid, hydrochloric acid, hydrobromic acid, and phosphoric acid. In aspecial embodiment of the invention, the treatment takes placepreferably in a mixture of strong acids; more preferably in a mixture ofmethanesulfonic acid and trifluoroacetic acid.

Electrophilic scavengers which are suitable for the treatment includeanisole, thioanisole, diphenyldisulfide, phenylbenzylsulfide,trimethoxybenzene, m-cresol, and 1,2-ethanediol. In a special embodimentaccording to the invention, a preferred electrophilic scavenger isthioanisole.

A preferred embodiment according to the invention is a method forpreparing a compound of Formula I,

wherein

* indicates a chiral carbon atom,

R₁ is optionally substituted aryl, or optionally substituted heteroaryl;and

R₃ is optionally substituted alkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl,

comprising reacting a compound of Formula II

with a compound of Formula III

R₂—SO₂—R′  Formula III

wherein

R′ is halo or OSO₂R₂; and

R₂ is optionally substituted aryl, or trihalomethyl,

in the presence of a base to form an aziridine compound of Formula IV.

A further preferred embodiment of the present invention is the method ofpreparing a compound of Formula I wherein R₁ is optionally substitutedheteroaryl; more preferably wherein R₁ is 3-chlorothien-2-yl.

Another further preferred embodiment of the invention is the method forpreparing the compound of Formula I wherein R₃ is alkyl; more preferablywherein R₃ is ethyl.

Another preferred embodiment according to the invention is a method forpreparing a compound of Formula I, comprising reacting the aziridine ofFormula IV with a compound of formula Li—R₁ to form a lithium compoundof Formula V,

or an aggregate thereof.

Another preferred embodiment according to the invention is a method forpreparing a compound of Formula I, comprising treating the lithiumcompound of Formula V with a strong acid or mixture of strong acids inthe presence of an electrophilic scavenger.

Preferred embodiments according to the invention are illustrated inScheme I.

If it is necessary or desirable to prevent cross-reaction betweenchemically active substituents (for example, any aryl or heteroarylgroup substituents) during the reactions according to the invention, thesubstituents may be protected by standard blocking groups which may besubsequently removed or retained, as required, by known methods, toafford the desired product. (See, for example, Green, Protective Groupsin Organic Synthesis, Wiley, New York (1982).) Selective protection ordeprotection also may be necessary or desirable to allow conversion orremoval of existing substituents, or to allow subsequent reaction toafford the final desired product.

The present invention is directed also to intermediates to[(1-optionally substituted aryl)- or (1-optionally substitutedheteroaryl)]-2-substituted ethyl-2-amines.

A compound embodiment according to the invention is the[(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridinehaving chirality at the 2-position, formed by the reaction of the of the2-amino-2-substituted ethyl alcohol with the sulfonyl halide oranhydride according to the method of the invention. A preferredembodiment of said aziridine is the compound of Formula IV. A specialembodiment of said aziridine includes1-p-toluenesulfonyl-2(R)-ethylaziridine.

Another compound embodiment according invention is the lithium salt ofan [(N-optionally substituted aryl)- or(N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or(optionally substituted heteroaryl)]-2-substituted alkyl-2-amine havingchirality at the 2-position formed by the reaction of the aziridine withan [(optionally substituted aryl)- or (optionally substitutedheteroaryl)] lithium compound according to the method of the invention.A preferred embodiment of this lithium salt is the compound of FormulaV. A special embodiment of the lithium salt is(R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt.

The present invention is further explained, but is in no way limited, bythe following examples.

EXAMPLE 1

Preparation of 1-p-toluenesulfonyl-2(R)-ethylaziridine

R-(−)-2-amino-1-butanol (99.96 g, 105 mL) and tert-butyl methyl ether(TBME) (277 g, 366 mL) are combined under a nitrogen atmosphere. Thismixture is stirred for several minutes and 10 N aqueous sodium hydroxide(449 mL) is added over a period of about 10 minutes. The reactionmixture is cooled to below 10° C. and a solution of p-toluene sulfonylchloride (TsCl) (464 g) in TBME (711 g) is added over a period of about50 minutes, maintaining the temperature of the reaction mixture at orbelow 32° C. After the addition is complete, the mixture is stirred forabout 30 minutes at 40° C., and water (900 mL) is added while coolingthe mixture to 25° C. The layers are separated and the organic layerwashed sequentially with water (150 g) and 25% aqueous sodium chloridesolution (300 g). Toluene (450 g) is added to the organic layer, and themixture distilled under reduced pressure, maintaining the temperature ofthe mixture at or below 45° C., until the water content of the mixtureis below about 0.1%. The resulting solution is used, without furthertreatment, for the preparation described in Example 2.

EXAMPLE 2 Preparation of(R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide Lithium Salt

Under a nitrogen atmosphere, a solution of 3-chlorothiophene (48.75 g)in TBME (291 g) is cooled to −10° C., and 2.5 M n-butyllithium inhexanes (151.3 mL) is added at such a rate that the reaction temperatureis maintained between 0 and 5° C. After the addition is complete, themixture is cooled to −5° C. and 1-p-toluenesulfonyl-2(R)-ethylaziridine(74.1 g, as a 56.9% (w/w) solution in TBME) is added at such a rate asto maintain the temperature of the reaction mixture below 9° C. (duringwhich time a solid precipitates). After about 5 minutes the mixture iscooled to 0° C. and the precipitate is collected by vacuum filtration,washed with 0° C. TBME (60 mL), and dried in vacuo at about 40° C., togive (R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt,m.p. 372° C. (dec.). MS (FAB), m/z 350, 352 (100%), ¹HNMR (200 Mhz,DMSO) δ 0.8 (t, 3H); 2.25 (s, 3H); 6.85 (d, 1H); 7.05 (d, 2H), 7.35 (d,2H).

EXAMPLE 3 Preparation of (R)-1-(3-chlorothien-2-yl)-2-aminobutane

(R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt (120g) is added in one portion to trifluoroacetic acid (470 g) in a vesselequipped with a condenser and mechanical stirrer. The temperature of themixture rises from about 25° C. to about 60° C. As the resultingsolution is cooling, thioanisole (85.2 g) is added, followed bymethanesulfonic acid (65.9 g). The reaction mixture is heated at 80° C.for about six hours. The mixture is cooled to 18° C. and toluene (600mL) is added. 6M aqueous sodium hydroxide solution (820 mL) is thenadded portionwise, with stirring, maintaining the reaction temperaturebelow 60° C. The layers are separated and the organic phase is washedwith water until the pH of the wash is 9; then it is washed with brine.The organic solution is cooled to 18° C. and toluene (200 mL) is added,followed by concentrated hydrochloric acid (42 mL). The resulting slurryis distilled at about 47° C. at 180 mm Hg to azeotropically removewater. After about 200 mL of toluene/water had been removed, the mixtureis cooled to 40° C., allowed to come to atmospheric pressure, thencooled to 15° C. over a 1 hour period. The solids which precipitate arecollected by vacuum filtration, washed with 60 mL of toluene and driedin vacuo to give (R)-1-(3-chlorothien-2-yl)-2-aminobutane as thehydrochloride salt, m.p. 137.6° C. MS (EI), m/z 190, 192 (10%); ¹HNMR(200 Mhz, DMSO) δ 0.9 (t, 3H); 1.6 (m, 2H); 7.05 (d, 1H); 7.6 (d, 2H),8.35 (s, 2H).

What is claimed is:
 1. A method for stereospecifically preparing a[(1-optionally substituted arylsoulfonyl)- or (1-optionally substitutedheteroaryl)]-2-substituted ethyl-2-amine, having chirality at the2-position, comprising reacting a 2-amino-2-substituted ethyl alcohol,having chirality at the 2-position, with an [(optionally substitutedaryl)- or (trihalomethyl) sulfonyl]-halide or anhydride in the presenceof a base to form an [(N-arylsulfonyl)- or(N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality atthe 2-position.
 2. A method according to claim 1 further comprisingreacting said aziridine with an [(optionally substituted arylsulfonyl)-or (optionally substituted heteroaryl)] lithium compound to form thelithium salt of an [(N-optionally substituted aryl)- or(N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or(optionally substituted heteroaryl)]-2-substituted alkyl-2-amine havingchirality at the 2-position.
 3. A method according to claim 1 forpreparing a compound of formula

wherein * indicates a chiral carbon atom, R₁ is optionally substitutedaryl, or optionally substituted heteroaryl; and R₃ is optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, or optionally substitutedheteroaralkyl; comprising reacting a compound of formula

with a compound of formula R₂—SO₂—R′ wherein R′ is halo or OSO₂R₂; andR₂ is optionally substituted aryl, or trihalomethyl, in the presence ofa base to form an aziridine compound of formula.


4. A method according to claim 3 further comprising reacting saidaziridine compound with a compound of formula Li—R₁, to form a lithiumcompound of formula

or an aggregate thereof, wherein R₁ is optionally substituted aryl, oroptionally substituted heteroaryl; R₂ is optionally substituted aryl, ortrihalomethyl; and R₃ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, or optionally substituted heteroaralkyl.
 5. A methodaccording to claim 3 wherein said reaction occurs in an aprotic organicsolvent.
 6. A method according to claim 5 wherein said aprotic organicsolvent is tert-butyl methyl ether.
 7. A method according to claim 3wherein R₂—SO₂—R′ is p-toluenesulfonyl chloride.
 8. A method accordingto claim 3 wherein said reaction occurs at about 25° C. to about 90° C.9. A method according to claim 3 wherein said reacting occurs at about25° C. to about 40° C.
 10. A method according to claim 3 wherein saidbase is selected from the group consisting of an aqueous alkali metalhydroxide, an aqueous alkali metal carbonate, and an aprotic organicamine.
 11. A method according to claim 3 wherein said base is aqueoussodium hydroxide.
 12. A method according to claim 3 wherein R₁ isoptionally substituted heteroaryl.
 13. A method according to claim 12wherein R₁ is 3-chlorothien-2-yl.
 14. A method according to claim 3wherein R₃ is alkyl.
 15. A method according to claim 14 wherein R₃ isethyl.
 16. A method according to claim 4 wherein reacting said aziridinecompound occurs in a solvent selected from the group consisting of anaprotic organic ether, aliphatic hydrocarbon, and an aromatichydrocarbon.
 17. A method according to claim 16 wherein said reactingsaid aziridine compound occurs in tert-butyl methyl ether.
 18. A methodaccording to claim 4 further comprising isolating said lithium compoundas a solid.
 19. A method according to claim 4 wherein said reactingoccurs at about −80° C. to about 50° C.
 20. A method according to claim19 wherein said reacting occurs at about −40° C. to about 50° C.
 21. A[(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridinehaving chirality at the 2-position.
 22. The aziridine compound accordingto claim 21 which is 1-p-toluenesulfonyl-2(R)-ethylaziridine.
 23. Alithium salt of an [(N-optionally substituted aryl)- or(N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or(optionally substituted heteroaryl)]-2-substituted alkyl-2-amine, havingchirality at the 2-position.
 24. The lithium salt according to claim 23of formula

or an aggregate thereof, wherein R₁ is optionally substituted aryl, oroptionally substituted heteroaryl; R₂ is optionally substituted aryl, ortrihalomethyl; and R₃ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, or optionally substituted heteroaralkyl.
 25. The lithiumcompound according to claim 24 which is(R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt.